β-hydroxybutyrate inhibits ferroptosis-mediated pancreatic damage in acute liver failure through the increase of H3K9bhb

Acute pancreatitis and hyperamylasemia are often seen in patients with acute liver failure (ALF). However, the underlying mechanisms remain elusive. This study describes pancreatic tissue damage and exocrine dysfunction in a mouse model of major-liver-resection-induced ALF. The analysis of 1,264 clinical cases of liver failure (LF) showed that the incidence of hyperamylasemia and hyperlipasemia in patients with LF is 5.5% and 20%, respectively. Metabolomic studies indicate that glutathione (GSH)-deficiency-caused ferroptosis contributes to pancreatic damage in mouse ALF. β-hydroxybutyrate (β-HB) is the only metabolite downregulated in the liver, serum, and pancreas. Our data suggest that β-HB protects pancreatic cells and tissues from GSH-deficiency-caused ferroptosis. β-HB administration in ALF mice restores the expression of ferroptosis-suppressor genes through histone H3 lysine 9 β-hydroxybutyrylation (H3K9bhb)-mediated chromatin opening. Our findings highlight β-HB as an endogenous metabolite regulating ferroptosis in the pancreas and extend our understanding of the pathophysiology of ALF-induced pancreatitis.